the vasoplegic syndrome following …©2017 mfmer | slide-1 the vasoplegic syndrome following...

©2017 MFMER | slide-1

The Vasoplegic Syndrome Following Cardiopulmonary Bypass

Patrick Wieruszewski, PharmD PGY2 Critical Care Resident

Pharmacy Grand Rounds December 12, 2017


Objectives

• Review the pathology and consequences of the cardiac vasoplegic syndrome

• Determine the role of salvage therapies for catecholamine-refractory cardiac vasoplegia

• Develop a treatment strategy for a vasoplegic patient following cardiopulmonary bypass


O2

CO2


↓SVR

↓BP

Protamine reversal

Exposure of blood to

CPB circuit

Blood transfusion

Complement

activation

CPB = cardiopulmonary bypass

SIRS = systemic inflammatory response syndrome

SVR = systemic vascular resistance

BP = blood pressure

Intraoperative

hypotension

↑ nitric oxide SIRS

+

↑ baroreceptor

stimulation

↑ nitric oxide

↓ vasopressin Aortic cross clamp

release

Reperfusion

syndrome

Smooth muscle

hyperpolarization

Omar et al. Am J Med Sci 2015;349:80-8.

Fischer et al. Semin Thoracic Surg 2010;22:140-4.


The Cardiac Vasoplegic Syndrome

• Incidence, ~5 to 45%

• Vasodilatory shock

• Good cardiac function

• Good circulatory volume

• Requires vasopressors

• Hypoperfusion

• Multi-organ failure

• Death

Omar et al. Am J Med Sci 2015;349:80-8.

Fischer et al. Semin Thoracic Surg 2010;22:140-4.


Cardiac Vasoplegia

Hypotension (↓↓ SVR)

High or normal cardiac output

Adequate fluid

resuscitation


Based on the physiologic changes during cardiopulmonary bypass, what would be your first line therapy for cardiac vasoplegia?

A. Catecholamines (i.e. norepinephrine)

B. Vasopressin

C. Methylene blue

D. Hydroxocobalamin (vitamin B12)

E. Ascorbic acid (vitamin C)


1st Line: Vasopressors

• Catecholamines

• Vasopressin

• Vasopressor-refractory

• Incidence unknown

• Consequences of high vasopressor rates

• Strong predictor of mortality

• Salvage therapies

• Methylene blue

• Hydroxocobalamin

• Ascorbic acid


↑SVR

↑BP

Protamine reversal


CPB circuit

Blood transfusion

Complement

activation

Intraoperative

hypotension


+

↑ baroreceptor

stimulation

↑ nitric oxide


release

Reperfusion

syndrome

Smooth muscle

hyperpolarization

Methylene Blue

Booth et al. Heart Surg Forum 2017;20:E234-8.


MB: Methylene Blue or Magic Bullet?

Design Multicenter, randomized, placebo-controlled (n = 56)

Population • MAP < 50 mmHg

• CVP < 5 mmHg

• PCWP < 10 mmHg

• CI > 2.5 L/min/m2

• SVR < 800 dyn/s/cm-5

• “vasopressor need”

Exclusion • None reported

Intervention • Methylene blue 1.5 mg/kg bolus (n = 28)

• Placebo (n = 28)

Levin et al. Ann Thorac Surg 2004;77:496-9.

MAP = mean arterial pressure

CVP = central venous pressure

PCWP = pulmonary capillary wedge pressure

CI = cardiac index


The Magic Bullet?

• Baseline norepinephrine rate ~ 0.7 mcg/kg/min

Levin et al. Ann Thorac Surg 2004;77:496-9.

0

5

10

15

20

25

30

1 2 3 4 6 12 24 36 48 72 96Nu

mb

er

of

Vaso

ple

gic

Pati

en

ts

Hours from Randomization

Methylene Blue

Placebo


Bolus Only

Leyh et al. J Thorac Cardiovasc Surg 2003;125:1426-31.

Mazzeffi et al. Ann Card Anaesth 2017;20:178-81.

• Retrospective cohort study (n = 54)

• Baseline norepinephrine ≥ 0.5 mcg/kg/min

• Bolus methylene blue 2 mg/kg

• ↓norepinephrine, ↑SVR at 1, 6, and 12 hours

• ↑ALT/AST

• In-hospital mortality, 6% (n = 3)

Leyh et al. 2003

• Retrospective cohort study (n = 88)

• Baseline N 12.5 mcg/min, V 0.09 units/min, E 7.4 mcg/min

• Bolus methylene blue 1-2 mg/kg

• ↓norepinephrine, ↑MAP

• ↑MAP, only variable associated with response

Mazzeffi et al. 2017

N = norepinephrine

E = epinephrine

V = vasopressin

ALT = alanine aminotransferase

AST = aspartate aminotransferase


Why Just One Dose?

• Retrospective cohort (n = 3608)

• Bolus 2 mg/kg then 0.5 mg/kg/h (n = 118)

Mehaffey et al. Ann Thorac Surg 2017;104:36-41.

0

1

2

3

4

5

6

7

8

9

10

4 8 12 16 20 24 28 32 36 40 44 48

Rate

(m

cg

/min

)

Hours from Administration

Norepinephrine

Epinephrine

58

60

62

64

66

68

70

72

74

4 8 12 16 20 24 28 32 36 40 44 48

MA

P (

mm

Hg

)

Hours from Administration


Have We Been Doing it Wrong?


Outcome OR (n = 48) ICU (n = 70) p-value

Adverse event 34 (71%) 53 (76%) 0.554

Transfusion 44 (92%) 58 (83%) 0.170

Length of stay (d) 12 (10, 19) 12 (6, 21) 0.447

Stroke 2 (4%) 4 (6%) 0.707

Renal failure 5 (10%) 20 (29%) 0.018

Reoperation 10 (21%) 21 (30%) 0.266

Sternal infection 1 (2%) 0 (0%) 0.219

Prolonged MV 11 (23%) 16 (23%) 0.994

30-day mortality 5 (10%) 20 (29%) 0.018


Limitations

• Low incidence of refractory vasoplegia

• No report of hemodynamic parameters

• Unknown amount of methylene blue received

• No description of vasopressor and hemodynamic behavior in early vs. late recipients



Methylene Blue

Fluid and tissue

discoloration

Hemolytic anemia

↓ Oximetry measurements

Serotonin Syndrome

Maximum dosage

Lavigne D. Semin Cardiothroac Vasc Anesth 2010;14:186-9.

Ramsay et al. Br J Pharmacol 2007;152:946-51.


↑SVR

↑BP

Protamine reversal


CPB circuit

Blood transfusion

Complement

activation

Intraoperative

hypotension


+

↑ baroreceptor

stimulation

↑ nitric oxide


release

Reperfusion

syndrome

Smooth muscle

hyperpolarization

Hydroxocobalamin

Weinberg et al. Free Radic Biol Med 2009;46:1626-32.


The Trendsetters

• 71 year-old male undergoing dual-valve repair, single-vessel coronary bypass, PFO closure

Roderique et al. Ann Thorac Surg 2014;97:1785-6.

Anesthesia Induction

N 0.07 mcg/kg/min

CPB Initiated

MAP 30-45 mmHg

N 0.1 mcg/kg/min

V 0.033 units/min

70 min of CPB

↓MAP with cardioplegia doses

5 grams IV hydroxocobalamin

After B12

MAP > 60 mmHg

↓N, V off

↓hypotension from cardioplegia

Post-op Day 1

Extubated

Off pressors

PFO = patent foramen ovale

N = norepinephrine

V = vasopressin


And The Followers…

Case

Surgery

Pressor

Requirements

Other

Interventions

Outcome

1 AVR, MVR N ?

V 0.1 units/min

MB 1 mg/kg + 0.5

mg/kg

Pressors weaned

POD 2,

extubated POD 3

2 LVAD

implantation

N 0.25 mcg/kg/min

V 0.04 units/min MB 1 mg/kg x 2

Pressors weaned on

ICU arrival

3 Aortic aneurysm

repair

N 0.45 mcg/kg/min

V 0.04 units/min

MB 0.375 mg/kg +

0.75 mg/kg

Discharged ICU on

POD 17

4 TVR, PFO

closure N 0.2 mcg/kg/min None

Discharged ICU on

POD 12

5 AVR, MVR, TVR

N 0.2 mcg/kg/min

E 0.1 mcg/kg/min

V 0.06 units/min

MB 3.3 mg/kg total

ECMO

Pressors weaned

POD 4

Burnes et al. J Cardiothorac Vasc Anesth 2017;31:1012-4.

Cai et al. Ann Card Anaesth 2017;20:462-4.

Zundel et al. J Cardiothorac Vasc Anesth 2017;Ahead of Print.

Cheungpasitporn et al. Clin Kidney J 2017;10:357-62.

AVR = aortic valve replacement

MVR = mitral valve replacement

TVR = tricuspid valve replacement

LVAD = left ventricular assist device

ECMO = extra corporeal membrane

oxygenation


Hydroxo-cobalamin

Cost,

Cost,

Cost

Sustained overt ↑MAP

Chromaturia Colorimetric

analysis interference

Hemodialysis alarm

interference

Zundel et al. J Cardiothorac Vasc Anesth 2017;Ahead of Print.

Cheungpasitporn et al. Clin Kidney J 2017;10:357-62.


Making The Case: Ascorbic Acid

L-tyrosine L-DOPA Dopamine

Norepinephrine Epinephrine

Carr et al. Crit Care 2015;19:418.

Rodemeister et al. Nutrition 2014;30:673-8.

Berger et al. Curr Opin Clin Nutr Metab Care 2015;18:193-201.


Ascorbic Acid in Cardiac Surgery

Case

Age/

Sex

Surgery

CPB

time (m)

Pressors at Vitamin

C initiation

Shock co-therapies

1 22/

M

Septal

myectomy 55

N 0.1 mcg/kg/min

E 0.02 mcg/kg/min

V 0.04 units/min

None

2 18/

M

LVAD

exchange 85

N 0.12 mcg/kg/min

E 0.08 mcg/kg/min

V 0.04 units/min

Hydrocortisone

3 67/

M

AVR, MVR,

TVR 196

N 0.3 mcg/kg/min

E 0.08 mcg/kg/min

V 0.04 units/min

Hydrocortisone,

methylene blue, VA

ECMO

Wieruszewski et al. Unpublished data, under peer review.


0

0.1

0.2

0.3

0.4

0.5

0.6

0 12 24 36 48 60 72

Tota

l V

asopre

ssors

* Case 1

Case 2

Case 3

0

0.1

0.2

0.3

0.4

0 12 24 36 48 60 72

Nore

pin

ephrine

Time From Vitamin C Initiation (h)

Va

so

pre

ss

or

Re

qu

ire

me

nts

(m

cg

/kg

/min

)

*Norepinephrine equivalents

N 0.1 mcg/kg/min = E 0.1 mcg/kg/min = V 0.04 units/min

Wieruszewski et al. Unpublished data, under peer review.


Limitations to Current Vasoplegia Data

• Inconsistent definitions of vasoplegia including the “vasopressor-refractory” cases

• Heterogeneous outcome variables

• Ideal dosing schema not truly known

• No comparison of salvage therapies

• Salvage therapy vs. first line?

• Scant reporting of adverse events


In The Meantime…

• Standardized vasoplegia definition

• Particularly concerning need for vasopressors

• Proposal: vasopressin then when norepinephrine > 0.1 mcg/kg/min

• Consider methylene blue or ascorbic acid

• Hydroxocobalamin as last resort

• Consider methylene blue administration in the operating theatre when coming off pump


Who May Benefit From OR Administration

• Left ventricular assist device

• Heart failure, especially known reduced ejection fraction

• Multiple comorbidities (including pre-existing dialysis dependence)

• Previous sternotomy and bypass exposure

• Extended durations of CPB and aortic cross clamp timing

• Not isolated vessel bypass cases


Future Directions for Vasoplegia Research

• Identification of patients at highest risk of vasopressor-refractory vasoplegia

• Elucidation of optimal administration timing

• Perioperative or intensive care unit

• Taking advantage of all mechanisms of CPB resulting vasoplegia

• Identification of novel agents


The cardiopulmonary bypass circuit does which of the following?

A. Invokes a SIRS-like immune response

B. Results in vasopressin deficiency

C. Increases nitric oxide synthesis

D. All of the above


Ascorbic acid is proposed to

A. Inhibit nitric oxide synthesis

B. Increase endogenous catecholamine synthesis

C. Agonize the angiotensin-renin system

D. All of the above


Conclusion

• The cardiac vasoplegia syndrome is a significant contributor of morbidity and mortality in cardiac surgical patients

• Salvage therapies are necessary in some vasoplegia cases, though data supporting their use is sparse

• Future research should focus on optimal timing of initiation of salvage therapies


“The ultimate objective of my work in this field has been to be able to operate inside the heart

under direct vision.” John H. Gibbon, Jr., M.D., 1954


The Vasoplegic Syndrome Following Cardiopulmonary Bypass

Patrick Wieruszewski, PharmD [email protected]

Pharmacy Grand Rounds December 12, 2017


Procurement Costs

MAYO CLINIC CONFIDENTIAL DATA

Example Treatment Procurement Cost

Methylene blue 1 mg/kg, then 1mg/kg x

6h, 80kg patient ~$43

Hydroxocobalamin 5 grams once ~$770

Ascorbic acid 1.5 gm q6h x 4 days ~$82


Risk of Serotonin Toxicity

Citalopram Milnacipran Clomipramine Cocaine Ondansetron Fentanyl

Escitalopram Venlafaxine Desipramine Ecstasy Palonosetron Buspirone

Fluoxetine Bupropion Doxepin LSD Metoclopraminde Sumatriptan

Fuvoxamine Vilazodone Imipramine Tramadol Dexfenfluramine Rizatriptan

Paroxetine Trazodone Maprotiline Meperidine Carbamazepine Naratriptan

Sertraline Nefazodone Nortriptyline St. John’s Wort Sibutramine Almotriptan

Desvenlafaxine Amitriptyline Protriptyline Dolasetron Dextromethorphan Zolmitraptan

Duloxetine Amoxapine Trimipramine Granisetron Cyclobenzaprine Pentazocine

Procarbazine Fenfluramine Phentermine Valproate Dextroamphetamine Methamphetamine

Levodopa Cardidopa Lithium Phenelzine Tranylcypromine Isocarboxazid

Moclobemide Safinamide Selegiline Rasagiline Linezolid Tedizolid


VANCS Trial 2017

• Vasopressin 0.01 to 0.06 units/min vs. norepinephrine 10 to 60 mcg/min to maintain MAP ≥ 65 mmHg

• V ↓ primary endpoint (mortality + severe complications)

• Driven by renal failure (36% v. 10%, p <0.0001)

• V ↓ time on pressors, ICU, and hospital stay

• V ↓ atrial arrhythmias (82% v. 64%, p = 0.0004)

• No differences in adverse events

Hajjar et al. Anesthesiology 2017;126:85-93.

the vasoplegic syndrome following …©2017 mfmer | slide-1 the vasoplegic syndrome following...

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